Thyroid hormones, such as L-thyroxine (T4) and 3,5,3′-triiodo-L-thyronine (T3), and their analogs such as GC-1, DITPA, Tetrac and Triac, regulate many different physiological processes in different tissues in vertebrates. It was previously known that many of the actions of thyroid hormones are mediated by the thyroid hormone receptor (“TR”). However, a novel cell surface receptor for thyroid hormone (L-thyroxine, T4; T3) has been described on integrin αvβ3. This receptor is at or near the Arg-Gly-Asp (RGD) recognition site on the integrin. The αvβ3 receptor is not a homologue of the nuclear thyroid hormone receptor (TR), but activation of this cell surface receptor results in a number of nucleus-mediated events, including the recently-reported pro-angiogenic action of the hormone and fibroblast migration in vitro in the human dermal fibroblast monolayer model of wound-healing.
Evidence that thyroid hormone can act primarily outside the cell nucleus has come from studies of mitochondrial responses to T3 and diiodothyronine (T2), from rapid onset effects of the hormone at the cell membrane, and from actions on cytoplasmic proteins. The recent description of a plasma membrane receptor for thyroid hormone on integrin αvβ3 has provided some insight into effects of the hormone on membrane ion pumps, such as the Na+/H+ antiporter, and has led to the description of interfaces between actions initiated at the membrane thyroid hormone receptor and nuclear events that underlie important cellular or tissue processes, such as, for example, angiogenesis and proliferation of certain tumor cells.
Integrin αvβ3 binds thyroid hormone near the Arg-Gly-Asp (RGD) recognition site of the integrin protein. The RGD site is involved in the protein-protein interactions linking the integrin to extracellular matrix (ECM) proteins such as vitronectin, fibronectin and laminin. (See Plow et al., 2000. J. Biol. Chem. 275:21785-88). Also initiated at the cell surface integrin receptor is the complex process of angiogenesis, which can be monitored in either a standard chick blood vessel assay or with human endothelial cells in a sprouting assay. This hormone-dependent process requires mitogen-activated protein kinase (MAPK; extracellular regulated kinase [ERK] 1/2) activation and the elaboration of vascular growth factors, including, but not limited to basic fibroblast growth factor (bFGF; FGF2), which is the downstream mediator of thyroid hormone's effect on angiogenesis. Tetrac blocks this action of T4 and T3, as does RGD peptide and other small molecules (such as XT-199) that mimic RGD peptide(s). Thus, it is possible that desirable neovascularization can be promoted with local application of thyroid hormone analogs, for example, in wound-healing, or that undesirable angiogenesis, such as that which supports tumor growth, can be antagonized with tetrac or triac.